A protein produced by intestinal cells kills certain bacteria by creating small holes in the microbes’ protective outer membranes. The human gut is home to trillions of bacteria that play an important role in digestive health. In some cases—such as inflammatory bowel disease—the body’s immune system reacts inappropriately to these microbes, irritating the intestinal lining. One way the body avoids this unwanted response is to limit contact between bacteria and the intestinal wall by killing any bacteria that get too close to the intestinal lining. However, it was not certain how the body accomplishes this.
A team of scientists tackled this problem by investigating proteins secreted by intestinal cells that are able to kill bacteria. The researchers focused on a protein called “RegIIIα,” which was previously found to be lethal to certain bacteria, although it was not certain how the protein actually killed the microbes. Additionally, RegIIIα is produced by intestinal cells when bacteria come in close contact with the lining of the gut, which suggests that RegIIIα could be used as a defense against intruding microbes. While investigating how RegIIIα kills bacteria, the scientists found that adding it to bacteria allowed a traceable dye to diffuse into the bacterial cells, which meant RegIIIα had caused the bacteria’s protective outer membrane to become leaky—something that can easily be fatal to most microbes. They saw the same leakiness when RegIIIα was added to artificial membranes made up of the same components that are in bacterial membranes. Other experiments showed that RegIIIα was creating tiny pores about one millionth of a millimeter in diameter in these membranes. The scientists used X-ray crystallography and electron microscopy to visualize the pores, and they found that each one was made up of six RegIIIα proteins that assemble to form a doughnut-shaped hole. This means that if a microbe gets too close to the intestinal wall, RegIIIα proteins produced by gut epithelial cells can insert themselves into the microbe, puncturing and killing it. The deadly effects of RegIIIα were not seen with all bacteria, however; some types of microbes have an extra chemical on their membrane surface that can protect them from this type of attack.
These findings show how the RegIIIα protein secreted by intestinal cells is part of an elaborate defense mechanism that helps create a bacteria-free buffer zone between gut bacteria and the intestinal wall, potentially preventing unwanted inflammatory reactions. Further research may shed light into how this system might break down during disease and, importantly, how it might be harnessed to prevent illness.
Mukherjee S, Zheng H, Mehabaw GD, Callenberg KM, Partch CL, Rollins D, Propheter DC, Rizo J, Grabe M, Jiang QX, Hooper LV. Antibacterial membrane attack by a pore-forming intestinal C-type lectin. Nature 505: 103-107, 2014.